The present invention relates to topical testosterone formulations, including methods for making and using such formulations. Accordingly, this invention covers the fields of pharmaceutical sciences and medicine.
Hormone replacement therapy has been used in the past to treat patients who have lost the ability to make the hormones or who have reduced hormone levels. Further, testosterone replacement therapy has been used to treat patients with abnormally low testosterone levels.
Numerous diseases currently afflict millions of people world wide that can be partially or wholly treated using testosterone therapy. Examples of such conditions include without limitation: AIDS wasting syndrome, hypogonadism, somatopause, andropause, viropause, other androgen deficiencies in males, anemia, kidney disease, benign prostatic hyperplasia, acne, infertility, constipation, dry eyes, periodontal disease, diabetic retinopathy and other retinopathies, Lupus Erythematosis or other autoimmune diseases, decreased bone density or osteoporosis, heart disease, hyperlipidemias and angina. Further, testosterone replacement therapy has been shown to provide positive health benefits to individuals deficient in testosterone, such as significantly increase muscle strength, mood, cognitive function and energy in men and women, increase insulin-like growth factor in serum and saliva, cause a temporary and reversible decrease in sperm count, and increase the penis size in prepubertal boys and hypogonadal adult men with micropenis.
A number of existing testosterone replacement therapies are known. Unfortunately, most known therapies suffer from one or more disadvantages that reduce treatment efficacy. For example, many known formulations present testosterone in such a manner that much of the dose becomes metabolized into a substantially different product in the plasma, such as estradiol. Further, the manner in which many testosterone formulations are delivered is painful, inconvenient, or provide an inflexible dosage amount, leading to poor patient compliance and subsequent unsuccessful hormone replacement levels.
Examples of specific known testosterone replacement therapies include oral delivery formulations, weekly or bimonthly depot or systemic injections, and topical formulations, such as fixed-dosage transdermal patches or topical gels. Oral administration of many androgens may not be considered a safe or desirable means of replacement because of first-pass hepatic effects, hepatotoxic side effects, and the rare condition of peliosis. Injectable testosterone formulations, including testosterone esters, have issues with pain and self administration, and further may produce toxic liver side effects and significantly fluctuating, hormone levels.
Recently, topical testosterone replacement therapy has been used to replace or increase levels of testosterone for men. Some of these topical applications include fixed dosage patches such as the patches marketed under the name of Testoderm TTS (Alza Pharmaceuticals, Mountain View, Calif.) and Androderm(copyright) (Watson Laboratories, Salt Lake City, Utah). Additional transdermal testosterone patches are disclosed in U.S. Pat. Nos. 4,704,282, 5,164,190 and 5,152,997. Further, one example of a low testosterone concentration gel is currently marketed under the name Androgel(copyright) (Solvay, Marietta, Ga.).
While fixed-dosage patches have the advantage of mimicking the physiologic production of testosterone through the use of the natural soy-based testosterone USP released in small amounts over 24 hours, the inflexibility in modifying or adjusting dose, may hamper long term treatment efforts. Other drawbacks are also known, such as skin irritation and adhesion problems. Further, the patches are visible on the skin, and while they may be covered with clothing, may be inconvenient or embarrassing when a wearer wishes to engage in various sporting activities which require the removal of clothing, such as swimming, etc.
Testosterone gels, such as the gel recited above, and other hormone replacement gels, such as those disclosed in U.S. Pat. No. 5,855,905, offer the potential for increased convenience to the user as well ease of administration and flexible dosing regimens, as compared to patch testosterone replacement therapies. Unfortunately, such gels also suffer from a number of disadvantages. First, most gels include the active hormones in a low concentration. As a result, the gel must be applied over a substantially large skin surface area in order to achieve therapeutic hormone levels. Such application increases the risk that other individuals in close contact with the patient may inadvertently absorb some of the testosterone. Additionally, much of the testosterone delivered using many known topical formulations, is preferentially aromatized into estradiol (E2), as opposed to being converted to dihydrotestosterone (DHT). Such elevated estrogen levels have been reported to coincide with a increased risk of cancer in many individuals. Other negative physiological effects of testosterone supplementation have been known to occur, such as interference with levels of prostate specific antigen (PSA), and luteinizing hormone.
Therefore, a testosterone replacement formulation which may be administered easily, painlessly, and over a small skin surface area, and which delivers testosterone with minimal estrogen production, or other negative physiological effects, continues to be sought through on-going research efforts.
Accordingly, the present invention provides a topical testosterone formulation that is capable of providing physiologic testosterone levels when applied to the skin in small amounts, and without significant formation of undesirable estrogen metabolites, such as estradiol. In one aspect, the topical testosterone formulation may include a modified poloxamer lecithin organogel carrier having admixed therein, an arginine ingredient in an amount of from about 0.1 to about 20% w/w, a tocopherol ingredient in an amount of from about 0.1 to about 20% w/w, and a therapeutically effective amount of testosterone. In one aspect, the testosterone may be micronized.
The specific type and amount of testosterone may vary depending on the particular disease or condition being treated, and may be added in any concentration required to achieve a particular result, so long as such concentration does not hinder the testosterone delivery and absorption by the skin. Different formulations may be designed to provide higher or lower testosterone doses. However, in one aspect, the amount of micronized testosterone may be from about 0.5% w/w to about 25% w/w of the formulation. In another aspect, the amount of micronized testosterone is from about 5% w/w to about 10% w/w of the formulation. In yet another aspect, the amount of micronized testosterone may be from about 10% w/w to about 20% w/w of the formulation.
As set forth more fully below, the purpose of the arginine ingredient is to facilitate the production of nitrous oxide (NO) and enhance vasodilation of capillaries. As a fundamental amino acid, arginine may be included in the formulation of the present invention in a variety of forms, including chelated, salt, and derivatized forms, as required in order to achieve a specific result. However, in one aspect, the arginine may be included as a salt form, and in another aspect, the ingredient may be L-arginine monochloride. Further, the arginine ingredient may be from about 5% w/w to about 10% w/w of the formulation.
The tocopherol ingredient is added to the formulation of the present invention as an aromatase inhibitor to help reduce, or minimize, the aromatic conversion of testosterone to an estrogen once the testosterone of the formulation is introduced into the serum. As is known in the art, tocopherol exists in two main forms, alpha tocopherol, and gamma tocopherol. Either form, or a combination of these forms, may be used in the formulation of the present invention. Further, the amount of tocopherol may be from about 5% w/w to about 10% w/w of the formulation.
Additionally, an effective amount of dehydroepiandrosterone (DHEA) may be included in the formulation of the present invention. In one aspect, the DHEA may be the sulfate form, dehydroepiandrosterone sulfate (DHEAS). DHEA administration has been linked to providing a variety of positive health benefits such as improved cognitive function, reduced obesity, etc. While DHEA may be included in the present invention in nearly any concentration required in order to achieve a particularly desired result, in one aspect, the amount of DHEA is from about 1% w/w to about 20% w/w of the formulation. In another aspect, the amount of DHEA may be from about 5% w/w to about 10% w/w of the formulation. Accordingly, in one aspect, the transdermal testosterone formulation may contain from about 50 to about 100 mg of testosterone, from about 10 to about 20 mg of DHEA, from about 1 to about 20 mg of L-arginine and from about 1 to 6 mg of alpha or gamma tocopherol in each 1000 mg of total formulation.
The topical formulation of the present invention may additionally include effective amounts of other ingredients, such as melatonin and oxytocin, which are thought to have various effects on androgenic activity, including the physiology and function of the prostate and other blood chemical interactions. For example, melatonin may be included for its various effects on human prostate epithelium. In one aspect, the amount of melatonin may be from about 1% w/w to about 20% w/w of the formulation. In another aspect, the amount of melatonin may be from about 5% w/w to about 10% w/w of the formulation. Additionally, oxytocin may be included for its capacity in modulating testosterone production, and its ability to monitor the conversion of testosterone to dihydrotestosterone (DHT). In one aspect, the amount of oxytocin may be from about 1% w/w to about 20% w/w of the formulation. In another aspect, the amount of oxytocin may be from about 5% w/w to about 10% w/w of the formulation.
In yet another embodiment of the present invention, progesterone may be included in an effective amount. Specifically, progesterone is thought to have anticancer effects with respect to prostate cancer, as is described in more detail below. Further, the addition of progesterone may be especially applicable when the topical formulation of the present invention is being used to temporarily and reversibly decreasing sperm count (i.e. contraceptive). In one aspect, the amount of progesterone may be from about 1% w/w to about 20% w/w of the formulation. In yet another aspect, the amount of progesterone may be from about 5% w/w to about 10% w/w of the formulation.
The present invention additionally encompasses a method of treating a disease or condition which is responsive to testosterone therapy. In general, such a method includes the step of administering a topical testosterone formulation as disclosed herein to the skin of a subject. A wide variety of diseases or conditions may be responsive to testosterone therapy, including without limitation: AIDS Wasting Syndrome, micropenis, somatopause, andropause, viropause, or androgen deficiency in adult males (ADAM), anemia from renal dialysis or chronic kidney disease, benign prostatic hyperplasia, acne, diabetes, infertility, periodontal disease, post anabolic steroid abuse, dry eyes, diabetic retinopathy, retinopathy, and Lupus Erythematosis decreased bone density (i.e. osteoporosis), hyperlipemia, predisposition toward prostrate cancer, heart disease, angina, and hypertension. Further, other symptoms resulting from testosterone deficiency may include without limitation, infrequent early morning erections, small penis size in prepubertal boys, subphysiologic levels of insulin-like growth factor (IGF-1, poor muscle strength, poor cognitive function, poor mood, and low energy. It is recognized that one or more of such symptoms may be the result of a naturally occurring disease or condition, or one that is brought on by habits or activities of the subject, such as opioid or steroid abuse.
A variety of routines and regimens may be used in order to effect treatment of the diseases or conditions recited above, and each specific situation may merit a customized dosage and duration, which can be readily determined by a physician, or other individual of ordinary skill in the art. However, in one aspect, the formulation may have a testosterone content of about 10% w/w, and be administered in an amount of from about 0.5 g to about 2 g once a day on a daily basis routine for at least about 30 days. Such a regime may achieve a serum testosterone level of from about 600 ng/dl to about 1200 ng/dl. Further, while the topical formulation may be applied to any location on the skin or mucosa, in one aspect, the formulation is administered to hairless skin along the rib area below the armpit and the underarm and/or to the scrotal skin.
As is known by those of ordinary skill in the art, testosterone levels may be measured in a variety of ways, including in the blood serum, and in saliva. One method for measuring the efficacy of hormone treatment is by measuring the levels achieved with the supplementation and comparing the level attained to levels considered to be within a normal range. The serum or saliva levels obtained at a give time interval, including peak serum levels, depend on a variety of factors, including the amount of hormone administered and the permeation rate at which the hormone permeates through the skin, and the rate at which the hormone is cleared from the skin and into the blood serum. However, in one aspect, the administration of the topical testosterone formulation of the present invention results in peak levels of serum or salivary testosterone within about 24 to about 36 hours after application. In another aspect, the administration may result in sufficiently high salivary levels of free testosterone and dihydrotestosterone to prevent the conversion of excess testosterone to estradiol.
The present invention also encompasses a method of minimizing aromatic conversion of testosterone to an estrogen during testosterone supplementation therapy. Such a method includes the steps of providing a topical testosterone formulation comprising a poloxamer lecithin organogel having admixed therein, an arginine ingredient in an amount of from about 0.1 to about 20% w/w, and a tocopherol ingredient in an amount of from about 0.1 to about 20% w/w, and a therapeutically effective amount of micronized testosterone, and administering the formulation to the skin of a subject. As recited above, the tocopherol is an aromatase inhibitor which aids in suppressing the aromatic metabolization of testosterone into an estrogen. As such, a greater portion of the testosterone which becomes metabolized is metabolized into dihydrotestosterone (DHT), and further free testosterone levels are increased. In some aspects, it is thought that the higher concentrations of free testosterone and DHT may further work to suppress the conversion of testosterone into estrogen.